Abstract Severe allergic asthmatic disease is characterized by significant airway structure changes and chronic inflammation predominated by eosinophils, mononuclear cells, and lymphocytes, and accompanied by mucus hypersecretion that depends upon the nature of the immune response. The most severe airways disease progresses through a continuum of responses ranging from manageable airway dysfunction to a steroid resistant state that is often a result of a severe exacerbation that is difficult to control. Over the more than 25 years of work in this area my laboratory has defined the role of numerous cytokines and chemokines that initiate and drive the pulmonary immune responses, identified innate immune molecules that shape the immune phenotype (TLRs, Notch), defined a role for respiratory viral infections that induce and exacerbate disease, examined epigenetic regulation of immune cell function, and more recently identified metabolic control of innate immune cell activation. Many of our previous discoveries have revealed potential therapeutic targets for pulmonary diseases, including studies in our 2nd NHLBI RO1 that examine stem cell factor and ILC2. One of our present NHLBI RO1 grants is examining the role of autophagy and cellular metabolism for innate immune cell function. Our most recent studies are addressing additional mechanisms linked to trained immunity within the lung, as well as development of lung responses that alter the structural and functional integrity of the lung. While we will be combining 2 RO1 with divergent themes, our overall objective of understanding how the pulmonary immune environment is developed and maintained during disease is central to all of our studies. Together, our past and ongoing investigations are revealing an integrated understanding of not only the immune responses during disease development, but also the long-term consequence of early disease and its relationship to altered lung function and development. Using this R35 mechanism, we will continue expanding on these areas of research that will be paradigm shifting. We will focus on specific goals including 1) determine how early RSV-induced responses in the lung alter the innate immune cell phenotype and induce lung structural changes that predisposes the lung to later allergic/asthmatic responses; 2) examine the role that stem cell factor (SCF) has on altering the activation of ILC2 populations in chronic pulmonary disease; and 3) investigate how cell metabolism alters immune cell development during disease to maintain and extend disease severity. Completion of these studies will provide new insights, establish new paradigms, and complete proof of concept studies needed to advance knowledge and validate new, therapeutically relevant mechanisms in clinical disease.